4D Molecular Therapeutics (FDMT) investor relations material

Study background and unmet need

• Cystic fibrosis lung disease remains a significant unmet need, with many patients ineligible for or unresponsive to CFTR modulators.

• Conventional gene therapy trials in CF failed due to ineffective gene delivery and expression.

• 4D-710 is a durable, redosable, variant-agnostic gene therapy using a novel AAV vector (A101) for aerosol delivery to airway cells.

• 4D-710 is the first known genetic medicine to demonstrate successful delivery and expression of the CFTR transgene throughout the airways after aerosol delivery.

• Cystic fibrosis affects over 105,000 people worldwide, with lung disease as the leading cause of morbidity and mortality.

Study design and objectives

• The AEROW Phase 1/2 trial evaluated dose-ranging cohorts (1e15, 2e15, 5e14, 2.5e14 vg) in adults with CF not eligible for modulators, focusing on dose finding, safety, and CFTR expression using lung biopsies and brushings.

• Multiple pulmonary endpoints, including FEV1, LCI, and CFQ-R, were used to assess clinical activity and inform phase II dose selection.

• Dose escalation started at 1e15 vector genomes, with lower doses explored after safety review and protocol amendments.

• The selected phase II dose is 2.5e14 vector genomes, based on safety, expression, and clinical activity data.

• Optional bronchoscopy at one year post-dosing was added to evaluate long-term durability of transgene expression.

Safety and tolerability

• 4D-710 was well tolerated in lower dose cohorts (5e14, 2.5e14 vg), with only mild, transient adverse events typical of nebulized therapies.

• No pulmonary 4D-710-related adverse events were observed after day 14; non-pulmonary events were mild and resolved without intervention.

• No new pulmonary or severe adverse events were seen in higher-dose cohorts.